1. Field
The present disclosure relates generally to the fields of diagnostic testing and imaging agents. The disclosure provides, for example, novel ligands for the preparation of MRI imaging agents, novel MRI imaging agents, compositions of the novel imaging agents, and methods of use thereof.
2. Description of Related Art
Molecular imaging is used for visualizing biological targets and to understand their complexities for diagnosis and treatment purposes. Through an accurate and real-time imaging of biological targets, a thorough understanding of the fundamental biological processes can be gained leading to the successful diagnose of various diseases (Weissleder, 2006). In particular, MRI imaging can be useful to help visualize those biological processes. Gadolinium is a known and well characterized T1 contrast agent with useful and important physical properties for use in MRI imaging agents. Unfortunately, this ion is highly toxic in a “free” state, and hence it is typically used as a thermodynamically stable and kinetically inert complex. Linear polyamine diethylenetriaminepentaacetic acid (DTPA) or polyazamacrocycle 1,4,7,-10-tetraazacyclododecane-1,4,7,10-tetraacetic acid derivatives (DOTA) with coordinating acetate arms have been commercially employed as they form sufficiently stable Gd(III) complexes. Unfortunately, these low molecular weight contrast agents are nonspecific, rapid renal excretion and extravasation, and they have relatively low relaxivity. Additionally, in order, to selectively target and identify other metal ions in solution additional functionality must be added to the contrast agent.
Zinc(II) ions in particular are of particular interest as zinc is the second most abundant trace element in mammalian tissues and plays an extensive role in controlling gene transcription and metalloenzyme function (Esqueda, et al., 2009). The prostate, pancreas, and brain are known to contain relatively large amounts of zinc ions relative to other issues in the body. Zinc and the movement of zinc ions has been associated with the formation of β-amyloids, the release of insulin by β-cells in the pancreas and changes in concentration in zinc is associated with formation of tumors particular in prostate tissue. As such, a method of in vivo imaging of zinc represents a key goal to helping understand these biological functions and associated disease states such as Alzheimer's disease, diabetes, and cancer.
Esqueda, et al. (2009) and US Patent Application 2011/0009605 reported an MRI based zinc targeting contrast agent which contained two dipicolylamine units conjugated to a Gd-chelated DOTA. This ligand in the presence of zinc shows increased relaxivity compared to the ligand without zinc present. Unfortunately, this particular ligand still has relatively low relaxivity giving and therefore a relatively high (˜100 μM) detection limit and thus improvements in the relaxivity of the complex can greatly improve the detection limit of the contrast agent which would be useful in a larger variety of biological applications.